This application is based on, and claims the benefit of, U.S. Provisional Application No. 60/441,843, filed Jan. 21, 2003, entitled COMPOSITIONS AND METHODS FOR TISSUE SPECIFIC TARGETING OF LENTIVIRUS VECTORS, which is incorporated herein by reference.
This invention was made with government support under grant numbers HL-53670 and AI-48034 awarded by the National Institutes of Health. The United States Government has certain rights in this invention.
This invention relates generally to methods of gene transfer and, more specifically to retroviral vectors that are specific for target cells.
Gene therapy approaches rely on efficient transfer of genes to the desired target cells. A wide variety of viral and nonviral vectors have been developed and evaluated for their efficiency of transduction, sustained expression of the transgene, and safety. Nonviral methods are inefficient and only attain a transient expression of the transgene. Viral vectors fail to achieve a satisfactory combination of efficacy of gene transfer, sustained transgene expression, and biosafety. For example, adenoviral vectors can allow highly efficient delivery of the transgene in most tissues in vivo, but expression is transient, primarily due to induction of an immune response against the transduced cells. Vectors derived from oncoretroviruses, such as the Moloney leukemia virus (MLV), exhibit characteristics favorable for sustained transgene expression and biosafety because they integrate the transgene in the genome of the target cells without transferring any viral gene. However, oncoretroviruses are severely restricted in their potential targets, as they can only transduce proliferating target cells that divide shortly after infection. Consequently, oncoretroviral vectors are limited to gene transfer in nondividing cells or employed in demanding ex vivo protocols of gene transfer. Furthermore, transcriptional shutoff of the transgene after in vivo reimplantation of the transduced cells can occur.
Lentivirus vectors based on human immunodeficiency virus (HIV) have been developed that can transduce nondividing cells both in vitro and in vivo. Such vectors can stably integrate into the host cell genome to effect long-term expression of the transgene and are free from significant cellular or humoral immune responses demonstrating their utility as delivery vehicles for genes in vivo or in vitro. As the etiological agent of acquired immunodeficiency syndrome (AIDS), safety in the use of lentiviral vectors has been enhanced through a variety of molecular engineering designs that inhibit the generation of replication-competent vectors through fortuitous recombination of vector gene components. Such engineering designs include removal of accessory genes which play a role in virulence, removal of trans-acting factors for transcription, the generation of self-inactivating vectors, separating the packaging signals from the functions required for vector production and splitting the packaging functions into multiple components. However, spectrum of infectivity of lentiviral vectors is limited to the tropism of their native envelope glycoproteins or to heterologous envelope proteins that transduce the same target cells as oncoretrovirus or other viral vectors used in gene delivery methods. Therefore, the ability to target nondividing cells, in general, and to target particular types and subclasses of nondividing cells, specifically, has been limited.
Thus, there exists a need for compositions that confer specific targeting capabilities onto lentiviral vectors and for methods of employing such vectors for the specific targeting of a therapeutic gene of interest. The present invention satisfies these needs and provides related advantages as well.